Psychoneuroendocrinology
Volume 34, Issue 7 , Pages 972-982 , August 2009

Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion

  • Stefan Wüst

      Affiliations

    • Department of Theoretical and Clinical Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany
    • Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany
    • Corresponding Author InformationCorresponding author at: Department of Genetic Epidemiology in Psychiatry, J5, 68159 Mannheim, Germany. Tel.: +49 621 17 03 6056; fax: +49 621 17 03 6055.
    • ,
  • Robert Kumsta

      Affiliations

    • Department of Theoretical and Clinical Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany
    • ,
  • Jens Treutlein

      Affiliations

    • Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany
    • ,
  • Josef Frank

      Affiliations

    • Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany
    • ,
  • Sonja Entringer

      Affiliations

    • Department of Theoretical and Clinical Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany
    • ,
  • Thomas G. Schulze

      Affiliations

    • Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany
    • ,
  • Marcella Rietschel

      Affiliations

    • Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany

Received 11 July 2008 ,Revised 19 December 2008 ,Accepted 23 January 2009.

References 

  1. Andrews MH, Matthews SG. Programming of the hypothalamo-pituitary-adrenal axis: serotonergic involvement. Stress. 2004;7:15–27
  2. Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. I. Affective disorders. Mol. Psychiatry. 2003;8:574–591
  3. Backhaus J, Junghanns K, Hohagen F. Sleep disturbances are correlated with decreased morning awakening salivary cortisol. Psychoneuroendocrinology. 2004;29:1184–1191
  4. Bartels M, Van den Berg M, Sluyter F, Boomsma DI, de Geus EJ. Heritability of cortisol levels: review and simultaneous analysis of twin studies. Psychoneuroendocrinology. 2003;28:121–137
  5. Bebbington PE, Dunn G, Jenkins R, Lewis G, Brugha T, Farrell M, et al. The influence of age and sex on the prevalence of depressive conditions: report from the National Survey of Psychiatric Morbidity. Psychol. Med. 1998;28:9–19
  6. Bethea CL. Regulation of progestin receptors in raphe neurons of steroid-treated monkeys. Neuroendocrinology. 1994;60:50–61
  7. Bhagwagar Z, Hafizi S, Cowen PJ. Increase in concentration of waking salivary cortisol in recovered patients with depression. Am. J. Psychiatry. 2003;160:1890–1891
  8. Blier P, de Montigny C. Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology. 1999;21:91S–98S
  9. Brummett BH, Boyle SH, Siegler IC, Kuhn CM, Ashley-Koch A, Jonassaint CR, et al. Effects of Environmental Stress and Gender on Associations among Symptoms of Depression and the Serotonin Transporter Gene Linked Polymorphic Region (5-HTTLPR). Behav. Genet. 2008;38:34–43
  10. Burgess LH, Handa RJ. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology. 1992;131:1261–1269
  11. Cahill L. Why sex matters for neuroscience. Nat. Rev. Neurosci. 2006;7:477–484
  12. Canli T, Lesch KP. Long story short: the serotonin transporter in emotion regulation and social cognition. Nat. Neurosci. 2007;10:1103–1109
  13. Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat. Rev. Neurosci. 2006;7:583–590
  14. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389
  15. Chida Y, Steptoe A. Cortisol awakening response and psychosocial factors: a systematic review and meta-analysis. Biol. Psychol. 2009;80:265–278
  16. Chrousos GP. Glucocorticoid therapy. In:  Flig P,  Frohman L editor. Endocrinology and Metabolism. 4th ed.. New York: McGraw-Hill; 2001;p. 609–632
  17. Clow A, Thorn L, Evans P, Hucklebridge F. The awakening cortisol response: methodological issues and significance. Stress. 2004;7:29–37
  18. Dallman MF, Viau VG, Bhatnagar S, Gomez F, Laugero K, Bell ME. Corticotropin-releasing factor, corticosteroids, stress, and sugar: energy balance, the brain, and behavior. In:  Pfaff DW,  Arnold AP,  Etgen AM,  Fahrbach SE,  Rubin RT editor. Hormones, Brain and Behavior, vol. 1.. New York: Academic Press; 2002;p. 571–631
  19. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat. Rev. Neurosci. 2005;6:463–475
  20. Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol. Bull. 2004;130:355–391
  21. Dinan TG. Serotonin and the regulation of hypothalamic–pituitary–adrenal axis function. Life Sci. 1996;58:1683–1694
  22. Dressendörfer RA, Kirschbaum C, Rohde W, Stahl F, Strasburger CJ. Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J. Steroid Biochem. Mol. Biol. 1992;43:683–692
  23. Federenko IS, Nagamine M, Hellhammer DH, Wadhwa PD, Wüst S. The heritability of hypothalamus pituitary adrenal axis responses to psychosocial stress is context dependent. J. Clin. Endocrinol. Metab. 2004;89:6244–6250
  24. Fries E, Dettenborn L, Kirschbaum C. The cortisol awakening response (CAR): facts and future directions. Int. J. Psychophysiol. 2009;72:67–73
  25. Gotlib IH, Joormann J, Minor KL, Hallmayer J. HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol. Psychiatry. 2008;63:847–851
  26. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry. 2003;160:636–645
  27. Hariri AR, Drabant EM, Munoz KE, Kolachana BS, Mattay VS, Egan MF, et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry. 2005;62:146–152
  28. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297:400–403
  29. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004;29:1765–1781
  30. Heinz A, Smolka MN, Braus DF, Wrase J, Beck A, Flor H, et al. Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation. Biol. Psychiatry. 2007;61:1011–1014
  31. Hensler JG. Serotonergic modulation of the limbic system. Neurosci. Biobehav. Rev. 2006;30:203–214
  32. Hoefgen B, Schulze TG, Ohlraun S, von Widdern O, Hofels S, Gross M, et al. The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biol. Psychiatry. 2005;57:247–251
  33. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol. Clin. Exp. Res. 2005;29:8–16
  34. Jabbi M, Korf J, Kema IP, Hartman C, van der Pompe G, Minderaa RB, et al. Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA. Mol. Psychiatry. 2007;12:483–490
  35. Jones BJ, Blackburn TP. The medical benefit of 5-HT research. Pharmacol. Biochem. Behav. 2002;71:555–568
  36. Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology. 2006;31:151–178
  37. Kalin NH, Shelton SE, Fox AS, Rogers J, Oakes TR, Davidson RJ. The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol. Psychiatry. 2008;13:1021–1027
  38. Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus–pituitary–adrenal axis. Psychosom. Med. 1999;61:154–162
  39. Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81
  40. Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol. Psychol. 2005;69:113–132
  41. Kudielka, B.M., Wüst, S., Kirschbaum, C., Hellhammer, D.H., 2007. The Trier Social Stress Test (TSST). In: Fink, G., Chrousos, G., Craig, I., de Kloet, E.R., Feuerstein, G., McEwen, B.S., Rose, N.R., Rubin, R.T., Steptoe, A. (Eds.), Encyclopedia of Stress, 2, revised edition. Elsevier, New York, Oxford.
  42. Kumsta R, Entringer S, Hellhammer DH, Wüst S. Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels. Psychoneuroendocrinology. 2007;32:1153–1157
  43. Kurina LM, Weiss LA, Graves SW, Parry R, Williams GH, Abney M, et al. Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women. J. Clin. Endocrinol. Metab. 2005;90:4747–4752
  44. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–1531
  45. Lesch KP, Meyer J, Glatz K, Flugge G, Hinney A, Hebebrand J, et al. The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication. J. Neural. Transm. 1997;104:1259–1266
  46. Liu K, Muse SV. PowerMarker: integrated analysis environment for genetic marker data. Bioinformatics. 2005;21:2128–2129
  47. Lotrich FE, Pollock BG, Ferrell RE. Polymorphism of the serotonin transporter: implications for the use of selective serotonin reuptake inhibitors. Am. J. Pharmacogenom. 2001;1:153–164
  48. Lowry CA. Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis. J. Neuroendocrinol. 2002;14:911–923
  49. Martin J, Cleak J, Willis-Owen SA, Flint J, Shifman S. Mapping regulatory variants for the serotonin transporter gene based on allelic expression imbalance. Mol. Psychiatry. 2007;12:421–422
  50. McCaffery JM, Bleil M, Pogue-Geile MF, Ferrell RE, Manuck SB. Allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cardiovascular reactivity in young adult male and female twins of European-American descent. Psychosom. Med. 2003;65:721–728
  51. McCormick CM, Linkroum W, Sallinen BJ, Miller NW. Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats. Stress. 2002;5:235–247
  52. Michaelovsky E, Frisch A, Rockah R, Peleg L, Magal N, Shohat M, et al. A novel allele in the promoter region of the human serotonin transporter gene. Mol. Psychiatry. 1999;4:97–99
  53. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215
  54. Murphy DL, Lerner A, Rudnick G, Lesch KP. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol. Interv. 2004;4:109–123
  55. Nakamura M, Ueno S, Sano A, Tanabe H. The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol. Psychiatry. 2000;5:32–38
  56. Patchev VK, Almeida OF. Gender specificity in the neural regulation of the response to stress: new leads from classical paradigms. Mol. Neurobiol. 1998;16:63–77
  57. Pecins-Thompson M, Bethea CL. Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience. 1999;89:267–277
  58. Pecins-Thompson M, Brown NA, Bethea CL. Regulation of serotonin re-uptake transporter mRNA expression by ovarian steroids in rhesus macaques. Brain Res. Mol. Brain Res. 1998;53:120–129
  59. Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL. Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J. Neurosci. 1996;16:7021–7029
  60. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat. Neurosci. 2005;8:828–834
  61. Portella MJ, Harmer CJ, Flint J, Cowen P, Goodwin GM. Enhanced early morning salivary cortisol in neuroticism. Am. J. Psychiatry. 2005;162:807–809
  62. Pruessner JC, Wolf OT, Hellhammer DH, Buske-Kirschbaum A, von Auer K, Jobst S, et al. Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sci. 1997;61:2539–2549
  63. Pruessner M, Hellhammer DH, Pruessner JC, Lupien SJ. Self-reported depressive symptoms and stress levels in healthy young men: associations with the cortisol response to awakening. Psychosom. Med. 2003;65:92–99
  64. Roberts AD, Wessely S, Chalder T, Papadopoulos A, Cleare AJ. Salivary cortisol response to awakening in chronic fatigue syndrome. Br. J. Psychiatry. 2004;184:136–141
  65. Roca CA, Schmidt PJ, Deuster PA, Danaceau MA, Altemus M, Putnam K, et al. Sex-related differences in stimulated hypothalamic–pituitary–adrenal axis during induced gonadal suppression. J. Clin. Endocrinol. Metab. 2005;90:4224–4231
  66. Rohleder N, Joksimovic L, Wolf JM, Kirschbaum C. Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biol. Psychiatry. 2004;55:745–751
  67. Schlotz W, Hellhammer J, Schulz P, Stone AA. Perceived work overload and chronic worrying predict weekend–weekday differences in the cortisol awakening response. Psychosom. Med. 2004;66:207–214
  68. Smith LJ, Henderson JA, Abell CW, Bethea CL. Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques. Neuropsychopharmacology. 2004;29:2035–2045
  69. Steiger H, Richardson J, Joober R, Gauvin L, Israel M, Bruce KR, et al. The 5HTTLPR polymorphism, prior maltreatment and dramatic-erratic personality manifestations in women with bulimic syndromes. J. Psychiatry Neurosci. 2007;32:354–362
  70. Swanson LW, Simmons DM. Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. J. Comp. Neurol. 1989;285:413–435
  71. Tjurmina OA, Armando I, Saavedra JM, Goldstein DS, Murphy DL. Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology. 2002;143:4520–4526
  72. Uhart M, Chong RY, Oswald L, Lin PI, Wand GS. Gender differences in hypothalamic–pituitary–adrenal (HPA) axis reactivity. Psychoneuroendocrinology. 2006;31:642–652
  73. Vamvakopoulos NC, Chrousos GP. Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction. J. Clin. Invest. 1993;92:1896–1902
  74. Viau V. Functional cross-talk between the hypothalamic–pituitary–gonadal and -adrenal axes. J. Neuroendocrinol. 2002;14:506–513
  75. von Have M, Oppelt PG, Müller A, Beckmann MW, Binder H. Kontrazeption. Geburtsh Frauenheilk. 2005;65:R173–R199
  76. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 2004;7:847–854
  77. Weich S, Sloggett A, Lewis G. Social roles and the gender difference in rates of the common mental disorders in Britain: a 7-year, population-based cohort study. Psychol. Med. 2001;31:1055–1064
  78. Weiss LA, Abney M, Cook EH, Ober C. Sex-specific genetic architecture of whole blood serotonin levels. Am. J. Hum. Genet. 2005;76:33–41
  79. Weiss LA, Pan L, Abney M, Ober C. The sex-specific genetic architecture of quantitative traits in humans. Nat. Genet. 2006;38:218–222
  80. Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol. Psychiatry. 2006;11:224–226
  81. Wessa M, Rohleder N, Kirschbaum C, Flor H. Altered cortisol awakening response in posttraumatic stress disorder. Psychoneuroendocrinology. 2006;31:209–215
  82. Wilhelm I, Born J, Kudielka BM, Schlotz W, Wüst S. Is the cortisol awakening rise a response to awakening?. Psychoneuroendocrinology. 2007;32:358–366
  83. Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, et al. Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology. 2003;28:533–541
  84. Wüst S, Federenko I, Hellhammer DH, Kirschbaum C. Genetic factors, perceived chronic stress, and the free cortisol response to awakening. Psychoneuroendocrinology. 2000;25:707–720
  85. Wüst S, Wolf J, Hellhammer DH, Federenko I, Schommer N, Kirschbaum C. The cortisol awakening response—normal values and confounds. Noise Health. 2000;2:79–88
  86. Yehuda R. Sensitization of the hypothalamic–pituitary–adrenal axis in posttraumatic stress disorder. Ann. NY Acad. Sci. 1997;821:57–75
  87. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol. Psychiatry. 2002;7:1115–1119
  88. Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E, et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol. Psychiatry. 2001;50:323–330

PII: S0306-4530(09)00029-8

doi: 10.1016/j.psyneuen.2009.01.011

Psychoneuroendocrinology
Volume 34, Issue 7 , Pages 972-982 , August 2009

Article Tools

* Image Usage & Resolution